The mammalian intestine is colonized by trillions of microorganisms that have co-evolved with the host in a symbiotic relationship. The presence of large numbers of symbionts near the epithelial ...surface of the intestine poses an enormous challenge to the host because it must avoid the activation of harmful inflammatory responses to the microorganisms while preserving its ability to mount robust immune responses to invading pathogens. In patients with inflammatory bowel disease, there is a breakdown of the multiple strategies that the immune system has evolved to promote the separation between symbiotic microorganisms and the intestinal epithelium and the effective killing of penetrant microorganisms, while suppressing the activation of inappropriate T cell responses to resident microorganisms. Understanding the complex interactions between intestinal microorganisms and the host may provide crucial insight into the pathogenesis of inflammatory bowel disease as well as new avenues to prevent and treat the disease.
Highlights • Genetic dissection of ENaC mediated sodium transport validate novel drug targets. • Signaling pathways controlling ENaC activity identifies novel drug targets. • Phamacodynamic and ...pharmacokinetics properties of next generation diuretics.
Mutation accumulation in somatic cells contributes to cancer development and is proposed as a cause of aging. DNA polymerases Pol ε and Pol δ replicate DNA during cell division. However, in some ...cancers, defective proofreading due to acquired POLE/POLD1 exonuclease domain mutations causes markedly elevated somatic mutation burdens with distinctive mutational signatures. Germline POLE/POLD1 mutations cause familial cancer predisposition. Here, we sequenced normal tissue and tumor DNA from individuals with germline POLE/POLD1 mutations. Increased mutation burdens with characteristic mutational signatures were found in normal adult somatic cell types, during early embryogenesis and in sperm. Thus human physiology can tolerate ubiquitously elevated mutation burdens. Except for increased cancer risk, individuals with germline POLE/POLD1 mutations do not exhibit overt features of premature aging. These results do not support a model in which all features of aging are attributable to widespread cell malfunction directly resulting from somatic mutation burdens accrued during life.
Nilsson's seminal work on Minoan-Myceanaean religion had its second edition in 1950 prior to the decipherment of Linear B; yet he found much in the archaeological record of the Bronze Age which he ...associated with later Greek religion.
This study seeks to clarify the nature of control in the context of information privacy to generate insights into the effects of different privacy assurance approaches on context-specific concerns ...for information privacy. We theorize that such effects are exhibited through mediation by perceived control over personal information and develop arguments in support of the interaction effects involving different privacy assurance approaches (individual self-protection, industry self-regulation, and government legislation). We test the research model in the context of location-based services using data obtained from 178 individuals in Singapore. In general, the results support our core assertion that perceived control over personal information is a key factor affecting context-specific concerns for information privacy. In addition to enhancing our theoretical understanding of the link between control and privacy concerns, these findings have important implications for service providers and consumers as well as for regulatory bodies and technology developers. PUBLICATION ABSTRACT
Transcription and translation require a high concentration of potassium across the entire tree of life. The conservation of a high intracellular potassium was an absolute requirement for the ...evolution of life on Earth. This was achieved by the interplay of P- and V-ATPases that can set up electrochemical gradients across the cell membrane, an energetically costly process requiring the synthesis of ATP by F-ATPases. In animals, the control of an extracellular compartment was achieved by the emergence of multicellular organisms able to produce tight epithelial barriers creating a stable extracellular milieu. Finally, the adaptation to a terrestrian environment was achieved by the evolution of distinct regulatory pathways allowing salt and water conservation. In this review we emphasize the critical and dual role of Na(+)-K(+)-ATPase in the control of the ionic composition of the extracellular fluid and the renin-angiotensin-aldosterone system (RAAS) in salt and water conservation in vertebrates. The action of aldosterone on transepithelial sodium transport by activation of the epithelial sodium channel (ENaC) at the apical membrane and that of Na(+)-K(+)-ATPase at the basolateral membrane may have evolved in lungfish before the emergence of tetrapods. Finally, we discuss the implication of RAAS in the origin of the present pandemia of hypertension and its associated cardiovascular diseases.
Nous sommes heureux que notre article sur la santé publique clinique1 ait reçu l’appui du Dr Shah2, qui mentionne également des éléments historiques importants au sujet de la santé publique clinique. ...Le Dr Shah a été le premier directeur d’un nouveau programme de résidence lancé en 1976 à l’Université de Toronto, soit le programme de résidence en médecine communautaire, qui porte maintenant le nom de programme de résidence en santé publique et en médecine préventive. Même s’il prétend ne pas avoir « su rassembler les cliniciens et les professionnels de la santé publique pour définir les éléments communs et les synergies nécessaires »2, nous sommes d’avis qu’il n’a pas échoué, car ses efforts ont inspiré ses étudiants (dont plusieurs ont corédigé l’article en question1). Tirant parti de son héritage important, les générations suivantes de cliniciens et de professionnels en santé publique ont fait des avancées sur le plan d’une collaboration efficace entre médecine clinique et santé publique.
We study the effects of failure to equilibrate the squared topological charge Q2 on lattice calculations of pseudoscalar masses and decay constants. The analysis is based on chiral perturbation ...theory calculations of the dependence of these quantities on the QCD vacuum angle θ. For the light-light partially quenched case, we rederive the known chiral perturbation theory results of Aoki and Fukaya, but using the nonperturbatively valid chiral theory worked out by Golterman, Sharpe and Singleton, and by Sharpe and Shoresh. We then extend these calculations to heavy-light mesons. Results when staggered taste violations are important are also presented. The derived Q2 dependence is compared to that of simulations using the MILC Collaboration’s ensembles of lattices with four flavors of dynamical highly improved staggered quarks. We find agreement, albeit with large statistical errors. These results can be used to correct for the leading effects of unequilibrated Q2, or to make estimates of the systematic error coming from the failure to equilibrate Q2. In an appendix, we show that the partially quenched chiral theory may be extended beyond a lower bound on valence masses discovered by Sharpe and Shoresh. Subtleties occurring when a sea-quark mass vanishes are discussed in another appendix.
Hypertension affects over 1.2 billion individuals worldwide and has become the most critical and expensive public health problem. Hypertension is a multifactorial disease involving environmental and ...genetic factors together with risk-conferring behaviors. The cause of the disease is identified in ∼10% of the cases (secondary hypertension), but in 90% of the cases no etiology is found (primary or essential hypertension). For this reason, a better understanding of the mechanisms controlling blood pressure in normal and hypertensive patients is the aim of very active experimental and clinical research. In this article, we review the importance of the renin-angiotensin-aldosterone system (RAAS) for the control of blood pressure, focusing on the evolution of the system and its critical importance for adaptation of vertebrates to a terrestrial and dry environment. The evolution of blood pressure control during the evolution of primates, hominins, and humans is discussed, together with the role of common genetic factors and the possible causes of the current hypertension pandemic in the light of evolutionary medicine.
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